Diabetic neuropathy is the most common disorder of human nerves and involves axons, Schwann cells and blood vessels through pathologic mechanisms which remain unknown. Our approach is to study toxic and metabolic neuropathies which best exemplify the individual lesions and to compare the pathologic changes to experimental diabetic neuropathy. We will also study the impact of increased endoneurial fluid pressure on the structure and function of nerve fibers in metabolic and toxic neuropathies. In galactosemic and diabetic neuropathy, analysis of microdrop samples of endoneurial fluid is planned to detect chemical disturbances which may give rise to abnormal nerve conduction. In sucrose and diabetic neuropathies, the effect of intra-axonal glycogen and polyglucosan deposits will be examined in relation to axonal transport. Hexachlorophene causes a dose related increase in endoneurial fluid pressure with subsequent axonal degeneration. We will measure nerve blood flow and axonal transport to evaluate the impact of acute increase in endoneurial fluid pressure in the endoneurial environment as shown in this neuropathy. In lead neuropathy, toxic changes of Schwann cells and microangiopathy take place. To investigate the role of endoneurial fluid as a vehicle for this toxin, electron probe microanalysis will be carried out to detect lead in microdrop samples of endoneurial fluid. Microangiopathic lesions in diabetic neuropathy will be studied in conjunction with studies of vascular changes which occur in myeloma neuropathy, produced by experimental plasma cell tumors which secrete immunoglobulins altering blood viscosity and damaging endothelial cells. By coordinating experimental techniques which explore different parameters of nerve structure and function with models for the individual pathologic changes, we hope to gain new insights into the mechanisms of diabetic neuropathy and improve our understanding of the endoneurial environment.